This invention relates to certain alkylene diamine-substituted heterocycles which selectively and potently bind mammalian neuropeptide Y (NPY) receptors. This invention also relates to pharmaceutical compositions comprising such compounds. It further relates to the use of such compounds in treating physiological disorders associated with an excess of neuropeptide Y, especially feeding disorders, some psychiatric disorders, and certain cardiovascular diseases.
Neuropeptide Y (NPY) is a 36 amino acid peptide first isolated in 1982 and subsequently found to be largely conserved across species. It belongs to a large family of peptides that includes, among others, peptide YY (PYY) and pancreatic peptide (PP). NPY is believed to be the most abundant peptide in the mammalian brain. It is also found in sympathetic neurons, and NPY-containing fibers have been found in peripheral tissues, such as around the arteries in the heart, the respiratory tract, the gastrointestinal tract, and the genitourinary tract. Central injection of NPY elicits a multitude of physiological responses, such as stimulation of feeding, increase in fat storage, elevation of blood sugar and insulin, anxiolytic behaviors, reduction in locomotor activity, hormone release, increase in blood pressure, reduction in body temperature, and catalepsy. In the cardiovascular system, NPY is believed to be involved in the regulation of coronary tone, while in the gastrointestinal tract, PYY is reported to cause inhibition of gastric acid secretion, pancreatic exocrine secretion, and gastrointestinal motility. These effects appear to be selectively mediated by various NPY receptors which currently include the Y1, Y2, Y3, Y4, Y5, and Y6 subtypes, in addition to the hypothetical Y1-like subtype. Selective peptidic agonists and antagonists have been identified for most of the subtypes, but few selective non-peptidic antagonists have been reported. The Y1 and Y5 receptor subtypes appear to be involved in appetite regulation, but their relative contribution to the modulation of food intake and energy expenditure remains unclear. The discovery of non-peptidic antagonists of the Y1 and/or Y5 receptor provides novel therapeutic agents, that are less prone to the shortcomings of the peptide antagonists, namely, for example, poor metabolic stability, low oral bioavailability, and poor brain permeability, for the treatment of obesity and cardiovascular disease.
The present invention also provides a general method to whereby mono-, bi-, or tricyclic heterocycles may be modified to obtain potent antagonists at the NPY1 receptor.
The present invention provides novel, potent, non-peptidic antagonists of NPY receptors, particularly, the NPY1 receptors, designed from a selection of mono-, bi-, or tri-cyclic heterocyclic cores.
The heterocyclic cores encompassed by the compounds of formula II-XV (shown below) have been previously described. The modifications made to these heterocyclic cores to obtain potent and selective NPY1 antagonists are entirely novel.
Compounds that interact with the Y1 receptor and inhibit the activity of neuropeptide Y at those receptors are useful in treating physiological disorders associated with an excess of neuropeptide Y1 including eating disorders, such as, for example, obesity and bulimia, and certain cardiovascular diseases, for example, hypertension.
This invention relates to novel compounds, compositions, and methods for the treatment of physiological disorders associated with an excess of neuropeptide Y. The novel compounds encompassed by the present invention are those of the formula I-XV. 
wherein
X is N or CR14;
W is S, O, or NR15;
Y is N or CR3;
E, F, and G are each, independently, CR3 or N;
I and J are each, independently,
Cxe2x95x90O, S, O, CR3R16 or NR15 when single bonded to both adjacent ring atoms, or
N, or CR3 when double bonded to an adjacent ring atom;
K is
N or CR3 when double bonded to L or J, or
O, S, Cxe2x95x90O, CR3R16, or NR15 when single bonded to both adjacent ring atoms, or
N or CR3 when double bonded to an adjacent ring atom;
L is
N or CR16 when single bonded to all atoms to which it is attached, or
C (carbon) when double bonded to K;
The 6- or 7-membered ring that contains I, J, K, and L may contain from 1 to 3 double bonds, from 0 to 2 heteroatoms, and from 0 to 2 Cxe2x95x90O groups, wherein the carbon atom of such groups are part of the ring and the oxygen atom is a substituent on the ring;
Q is O or NR15;
R1 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7; C1-C6 cyanoalkyl, NR8R9, C1-C6 alkyl-NR8R9;
R2 is H,
C1-C6 alkyl which optionally forms a C3-C6 aminocarbocycle or a C2-C5 aminoheterocycle with A or B, each optionally substituted at each occurrence with R7,
C3-C10 cycloalkyl, or
(C3-C10 cycloalkyl) C1-C6 alkyl;
or R2 and R6 jointly form with the 2 nitrogen atoms to which they are bound a C2-C5 aminoheterocycle optionally substituted at each occurrence with R7;
A is (CH2)m where m is 1, 2 or 3 and is optionally mono- or di-substituted on each occurrence with C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C6 alkenyl, C1-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7; C1-C6 cyanoalkyl, NR8R9, C1-C6 alkyl-NR8R9,
or A and B jointly form a C3-C6 carbocycle, optionally substituted at each occurrence with R7 
or, as mentioned above, A and R2 jointly form a C3-C6 aminocarbocycle or a C2-C5 aminoheterocycle optionally substituted at each occurrence with R7;
B is (CH2)n where n is 1, 2 or 3 and is optionally mono- or di-substituted on each occurrence with C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halo, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7; C1-C6 cyanoalkyl NR8R9, C1-C6 alkyl-NR8R9,
or, as mentioned above, B and A jointly form a C3-C6 carbocycle, optionally substituted at each occurrence with R7 
or, as mentioned above, B and R2 jointly form a C3-C6 aminocarbocycle or a C2-C5 aminoheterocycle optionally substituted at each occurrence with R7;
R3 and R16 are selected independently at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, cyano, halogen, C1-C6 haloalkyl, OR7, C1-C6 alkyl-OR7, C1-C6 cyanoalkyl, NR8R9, C1-C6 alkyl-NR8R9;
R4 is selected from aryl or heteroaryl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C6 alkenyl, halogen, C1-C6 haloalkyl, trifluromethylsulfonyl, OR7, C1-C6 alkyl-OR7, NR8R9, C1-C6 alkyl-NR8R9, CONR8R9, C1-C6 alkyl-CONR8R9, COOR7, C1-C6 alkyl-COOR7, CN, C1-C6 alkyl-CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that at least one of the positions ortho or para to the point of attachment of the aryl or heteroaryl ring to the heterocyclic core is substituted;
R5 is selected from:
C1-C6 alkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, each of which is substituted with 1 to 5 groups independently selected at each occurrence from halo, C1-C2 haloalkyl, OR7, cyano, NR8R9, CONR8R9, COOR7, SO2NR8R9, SO2R7, NR11COR12, NR11SO2R7;
C1-C6 arylalkyl, C1-C6 heteroarylalkyl, C5-C8 arylcycloalkyl, or C5-C8 heteroarylcycloalkyl, where aryl is phenyl or naphthyl, and heteroaryl is 2-, 3-, or 4-pyridyl, 2-, 4- or 5-pyrimidinyl, triazinyl, 1-, 2- or 4-imidazolyl, 2-, 4-, or 5-oxazolyl, isoxazolyl, indolyl, pyrazolyl, quinolyl, isoquinolyl, 2-, 4-, or 5-thiazolyl, benzothiadiazolyl, 1-, 3- or 4-pyrazolyl, 1-, 3- or 4-triazolyl, 2-triazinyl, 2-pyrazinyl, 2-, or 3-furanyl, 2-, or 3-thienyl, 2-, or 3-benzothienyl, or 1-, 2- or 5-tetrazolyl, each of which is optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C6 alkenyl, halogen, C1-C6 haloalkyl, trifluromethylsulfonyl, OR7, NR8R9, C1-C6 alkyl-OR7, C1-C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that 2 adjacent substituents can optionally form together a C3-C10 cycloalkyl ring, a C3-C10 cycloalkenyl ring or a heterocycloalkyl ring;
C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C3-C10 cycloalkenyl, C2-C6 alkenyl, C2-C6 alkynyl, each of which is optionally with 1 to 6 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C6 alkenyl, halogen, C1-C6 haloalkyl, OR7, NR8R9, with the proviso that when two OR7 or NR8R9 substituents are geminally located on the same carbon R7 is not H and they can form together a C2-C4 ketal, oxazoline, oxazolidine, imidazoline, or imidazolidine heterocycle, C1-C6 alkyl-OR7, C1-C6 alkyl-NR8R9, CONR8R9, COOR7, CN, oxo, hydroximino, C1-C6 alkoximino, SO2NR8R9, SO2R7, heterocycloalkyl, aryl, heteroaryl, where aryl or heteroaryl is optionally substituted with 1 to 5 substituents independently selected at each occurrence from C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C6 alkenyl, halogen, C1-C6 haloalkyl, trifluromethylsulfonyl, OR7, NR8R9, C1-C6 alkyl-OR7, C1-C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that 2 adjacent substituents can optionally form together a C3-C10 cycloalkyl ring, a C3-C10 cycloalkenyl ring or a heterocycloalkyl ring;
aryl or heteroaryl, optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C6 alkenyl, halogen, C1-C6 haloalkyl, trifluromethylsulfonyl, OR7, NR8R9, C1-C6 alkyl-OR7, C1-C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7, aryl, heteroaryl, heterocycloalkyl, 3-, 4-, or 5-(2-oxo-1,3-oxazolidinyl), with the proviso that 2 adjacent substituents can optionally form together a C3-C10 cycloalkyl ring, a C3-C10 cycloalkenyl ring or a heterocycloalkyl ring; or
3- or 4-piperidinyl, 3-pyrrolidinyl, 3- or 4- tetrahydropyranyl, 3-tetrahydrofuranyl, 3- or 4-tetrahydropyranyl, 3-tetrahydrofuranyl, 3- or 4-tetrahydrothiopyranyl, 3- or 4-(1,1-dioxo) tetrahydrothiopyranyl, 1-azabicyclo[4.4.0]decyl, 8-azabicyclo[3.2.1]octanyl, norbornyl, quinuclidinyl, each optionally substituted with 1 to 5 substituents independently selected at each occurrence from R7, C1-C6 alkyl-OR7, C1-C6 alkyl-NR8R9, CONR8R9, COOR7;
R6 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C4 alkenyl, C1-C6 arylalkyl, C1-C6 heteroarylalkyl where aryl or heteroaryl are optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1-C6 haloalkyl, OR13, NR8R9, C1-C6 alkyl-OR13, C1-C6 alkyl-NR8R9, CONR8R9, COOR7, CN, SO2NR8R9, SO2R7,
or R6 and R2, as mentioned above, jointly form, with the 2 nitrogen atoms to which they are bound, a C2-C5 aminoheterocycle optionally substituted at each occurrence with R7;
R7 is H, C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C3 haloalkyl,
or heterocycloalkyl, C1-C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl each optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, C1-C6 haloalkyl, OR13, NR8R9, C1-C6 alkyl-OR13, C1-C6 alkyl-NR8R9, CONR8R9, COOR13, CN, SO2NR8R9, SO2R13, with the proviso that when R7 is SO2R13, R13 cannot be H;
R8 and R9 are independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, C2-C6 alkenyl, C3-C10 cycloalkenyl, C2-C6 alkynyl, heterocycloalkyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl, or R8 and R9, taken together, can form a C3-C6 aminocarbocycle or a C2-C5 aminoheterocycle each optionally substituted at each occurrence with with C1-C6 alkyl, C3-C10 cycloalkyl, C3-C10 cycloalkenyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C1-C3 haloalkyl, or heterocycloalkyl, C1-C8 alkylsulfonyl, arylsulfonyl, heteroarylsulfonyl, C1-C8 alkanoyl, aroyl, heteroaroyl, aryl, heteroaryl, C1-C6 arylalkyl or C1-C6 heteroarylalkyl;
R11 is selected from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl;
R12 is selected from H, aryl, heteroaryl, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, optionally substituted with OR7, NR8R9, C3-C6 aminocarbocycle, or C2-C5 aminoheterocycle;
R13 is independently selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 haloalkyl, with the proviso that for SO2NR8R9, SO2R13, R13 cannot be H;
R14 is H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10cycloalkyl) C1-C6 alkyl, C2-C4 alkenyl, C2-C4 alkynyl, halo, or CN;
R15 is selected at each occurrence from H, C1-C6 alkyl, C3-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C2-C6 alkyl-OR7, C2-C6 cyanoalkyl, C2-C6 alkyl-NR8R9;
or a pharmaceutically acceptable salt, hydrate, or prodrug thereof.
Preferred compounds of the present invention are those where X is N or CH, R1 is H, C1-C6 alkyl, C3-C10 cycloalkyl, or (C3-C10 cycloalkyl) C1-C6 alkyl; and R6 is H, C1-C6 alkyl, C3-C10 cycloalkyl, or (C3-C10 cycloalkyl) C1-C6 alkyl. Additional preferred compounds are those wherein R6 is phenethyl optionally substituted with one or two substituents selected from alkyl and alkoxy, tetrahydropyranyl and piperidinyl optionally substituted by a heterocycle. Other preferred compounds are those wherein R4 is phenyl, optionally substituted in one, two or three positions by alkyl, alkoxy or halogen.
This invention also encompasses, in additional embodiments, the novel compounds of formula I-XV, and the salts and solvates thereof, as well as pharmaceutical formulations comprising a compound of formula I-XV, or a pharmaceutically acceptable salt or solvate thereof, in combination with one or more pharmaceutically acceptable carriers, excipients, or diluents thereof.
This invention also encompasses methods to treat physiological disorders associated with an excess of neuropeptide Y, such as eating and cardiovascular disorders, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of the formula I-XV.
This invention also encompasses methods of selectively inhibiting binding of NPY1 receptors, which comprises contacting a compound of formula I-XV with neuronal cells, wherein the compound is present in an amount effective to produce a concentration sufficient to inhibit binding of NPY1 receptors in vitro.
As such, the present invention also provides a method to convert heterocyclic cores of formula Ia to XVa where X, E, F, G, W, I, J, K, L, Q, R1, R3, R4, R15 and R16 are defined above, into compounds that potently and selectively interact with NPY1 receptors by substituting the n-position of heterocycles of formula Ia-XVIa with a diamine group of formula N[R2]xe2x80x94Axe2x80x94Bxe2x80x94N[R6]xe2x80x94R5 where R2, A, B, R6, and R5 are defined above. 
This invention relates to certain alkylene diamine-substituted heterocycles which selectively and potently bind mammalian neuropeptide Y (NPY) receptors, those of formula I-XV, which are novel and useful neuropeptide Y receptor antagonists.
In the present description, the compounds of formula I-XV may be generically described under formula A, where R1, R2, R4, R5, R6, X, Y, A, and B are defined above. 
In certain situations, the compounds of formula I-XV may contain one or more asymmetric carbon atoms, so that the compounds can exist in different stereoisomeric forms. These compounds can be, for example, racemates or optically active forms. In these situations, the single enantiomers, i.e., optically active forms, can be obtained by asymmetric synthesis or by resolution of the racemates. Resolution of the racemates can be accomplished, for example, by conventional methods such as crystallization in the presence of a resolving agent, or chromatography, using, for example a chiral HPLC column.
Representative compounds of the present invention, which are encompassed by formula I-XV, include, but are not limited to the compounds in Examples 1-56 and their pharmaceutically acceptable acid addition salts. In addition, if the compound of the invention is obtained as an acid addition salt, the free base can be obtained by basifying a solution of the acid salt. Conversely, if the product is a free base, an addition salt, particularly a pharmaceutically acceptable addition salt, may be produced by dissolving the free base in a suitable organic solvent and treating the solution with an acid, in accordance with conventional procedures for preparing acid addition salts from base compounds.
Non-toxic pharmaceutical salts include salts of acids such as hydrochloric, phosphoric, hydrobromic, sulfuric, sulfinic, formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric, tartaric, maleic, hydroiodic, alkanoic such as acetic, HOOCxe2x80x94(CH2)nxe2x80x94COOH where n is 0-4, and the like. Those skilled in the art will recognize a wide variety of non-toxic pharmaceutically acceptable addition salts.
The present invention also encompasses the acylated prodrugs of the compounds of formula I-XV. xe2x80x9cProdrugsxe2x80x9d are considered to be any covalently bonded carriers which release the active parent drug of formula I-XV in vivo when such prodrug is administered to a mammalian subject. Prodrugs of the compounds of the invention are prepared by modifying functional groups present in the compounds in such a way that the modifications are cleaved, either in routine manipulation or in vivo to the parent compounds. Prodrugs include compounds wherein hydroxy, amine, or sulfhydryl groups are bonded to any group that, when administered to a mammalian subject, cleaves to form a free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to, acetate, formate, and benzoate derivatives of alcohol and amine functional groups in the compounds of formula I-XV; and the like. Those skilled in the art will recognize various synthetic methodologies which may be employed to prepare non-toxic pharmaceutically acceptable addition salts and acylated prodrugs of the compounds encompassed by formula I-XV.
Where a compound exists in various tautomeric forms, the invention is not limited to any one of the specific tautomers. The invention includes all tautomeric forms of a compound.
By xe2x80x9cheteroatomxe2x80x9d in the present invention is meant oxygen or sulfur, or a nitrogen atom optionally substituted by C1-C6 lower alkyl, C1-C6 arylalkyl, C1-C10 cycloalkyl, (C3-C10 cycloalkyl) C1-C6 alkyl, C2-C8 alkanoyl, C1-C6 sulfonyl.
By xe2x80x9calkylxe2x80x9d, xe2x80x9clower alkylxe2x80x9d, or xe2x80x9cC1-C6 alkylxe2x80x9d in the present invention is meant straight or branched chain alkyl groups having 1-6 carbon atoms, such as, for example, methyl, ethyl, propyl, isopropyl, n-butyl, sec-butyl, tert-butyl, pentyl, 2-pentyl, isopentyl, neopentyl, hexyl, 2-hexyl, 3-hexyl, and 3-methylpentyl.
By xe2x80x9ccycloalkylxe2x80x9d, or xe2x80x9cC3-C10 cycloalkylxe2x80x9d in the present invention is meant alkyl groups having 3-10 carbon atoms forming a mono-, bi-, or polycyclic ring system, such as, for example, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, norbornyl, and the like.
By xe2x80x9c(cycloalkyl)alkylxe2x80x9d, xe2x80x9clower (cycloalkyl)alkylxe2x80x9d, or (C3-C10 cycloalkyl) C1-C6 alkyl in the present invention is meant a straight or branched alkyl substituent formed of 1 to 6 carbon atoms attached to a mono-, bi, or polycyclic ring system having 3-10 carbon atoms, such as, for example, cyclopropylmethyl, cyclobutylmethyl, cyclopentylmethyl, cyclohexylmethyl, cycloheptylmethyl, and the like.
The term xe2x80x9cC2-C6 alkenylxe2x80x9d in the present invention means hydrocarbon chains having 2 to 6 carbons in a straight or branched arrangement and containing one or more unsaturated carbon-carbon double bonds which may occur in any stable point along the chain, such as, for example, ethenyl, allyl, isopropenyl, and the like.
By xe2x80x9ccycloalkenylxe2x80x9d or xe2x80x9cC3-C10 cycloalkenylxe2x80x9d in the present invention is meant alkyl groups having 3-10 carbon atoms forming a mono-, bi, or polycyclic ring system having 3-10 carbon atoms and containing one or more carbon-carbon double bonds which may occur in any stable point in the ring, such as, for example, cyclopentenyl, cyclohexenyl, or cycloheptenyl.
The term xe2x80x9cC2-C6 alkynylxe2x80x9d in the present invention means hydrocarbon chains having 2 to 6 carbons in a straight or branched arrangement and containing one or more unsaturated carbon-carbon triple bonds which may occur in any stable point along the chain, such as, for example, ethynyl, propargyl, and the like.
The term xe2x80x9carylxe2x80x9d in the present invention means a monocyclic or bicyclic aromatic group having preferably 6 to 10 carbon atoms, such as, for example, phenyl or naphthyl.
The term xe2x80x9cheteroarylxe2x80x9d in the present invention means an aryl group in which one or more of the ring(s) carbon atoms have been replaced with a heteroatom. Such groups preferably have 4 to 10 carbon atoms and 1 to 4 heteroatoms, such as, for example, pyridyl, pyrimidinyl, triazinyl, imidazolyl, oxazolyl, isoxazolyl, indolyl, pyrrolyl, pyrazolyl, quinolinyl, isoquinolinyl, thiazolyl, benzothiadiazolyl, triazolyl, triazinyl, pyrazinyl, furanyl, thienyl, benzothienyl, benzofuranyl, tetrazolyl.
The term xe2x80x9cheterocyclylxe2x80x9d, xe2x80x9cheterocyclexe2x80x9d or xe2x80x9cheterocycloalkylxe2x80x9d in the present invention means a saturated or partially saturated heteroaryl group.
By xe2x80x9cC1-C6 arylalkylxe2x80x9d or xe2x80x9cC1-C6 heteroarylalkylxe2x80x9d in the present invention is meant a branched or straight-chain alkyl group having 1-6 carbon atoms and substituted on one of the carbon atoms by an optionally substituted aryl or heteroaryl ring, such as, for example, benzyl, phenethyl, methylpyridyl, ethylpyridyl, and the like.
By xe2x80x9cC5-C8 arylcycloalkylxe2x80x9d in the present invention is meant cycloalkyl groups having 5-8 carbon atoms and fused to an aryl group, such as, for example, 1,2,3,4 tetrahydronaphthalenyl, 2,3-dihydrobenzothienyl, or 2,3-dihydobenzofuranyl.
By xe2x80x9cC5-C8 heteroarylcycloalkylxe2x80x9d in the present invention is meant cycloalkyl groups having 5-8 carbon atoms fused to a heteroaryl group, such as, for example, 1,2,3,4 tetrahydroquinolyl, 2,3-dihydrobenzothienyl, 2,3-dihydobenzofuranyl, or indolinyl.
By xe2x80x9calkoxyxe2x80x9d, xe2x80x9cC1-C6 alkoxyxe2x80x9d, or xe2x80x9cC1-C6 alkyloxyxe2x80x9d in the present invention is meant straight or branched chain alkoxy groups having 1-6 carbon atoms, such as, for example, methoxy, ethoxy, propoxy, isopropoxy, n-butoxy, sec-butoxy, tert-butoxy, pentoxy, 2-pentyl, isopentoxy, neopentoxy, hexoxy, 2-hexoxy, 3-hexoxy, and 3-methylpentoxy.
By xe2x80x9ccycloalkoxyxe2x80x9d, xe2x80x9cC3-C10 cycloalkoxyxe2x80x9d, or xe2x80x9cC3-C10 cycloalkyloxyxe2x80x9d in the present invention is meant a group formed by an oxygen atom attached to a mono-, bi, or polycyclic ring system having 3-10 carbon atoms, such as, for example, cyclopropoxy, cyclobutoxy, cyclopentoxy, cyclohexoxy, or cycloheptoxy.
By xe2x80x9c(cycloalkyl)alkyloxyxe2x80x9d, xe2x80x9c(C3-C10 cycloalkyl) C1-C6 alkoxyxe2x80x9d, or xe2x80x9c(C3-C10 cycloalkyl) C1-C6 alkyloxyxe2x80x9d in the present invention is meant a group formed by an oxygen atom attached to a 1-6 carbon chain linked to a mono-, bi, or polycyclic ring system having 3-10 carbon atoms, such as, for example, cyclopropylmethyloxy, cyclobutylmethyloxy, cyclopentylmethyloxy, cyclohexylmethyloxy, cycloheptylmethyloxy, and the like.
By xe2x80x9cC3-C6 aminocarbocyclexe2x80x9d is meant a cyclic amino group formed by a nitrogen contained in a ring having 3 to 6 carbon atoms, such as, for example, azetidino, pyrrolidino, piperidino, perhydroazepino.
By xe2x80x9cC2-C5 aminoheterocyclexe2x80x9d is meant a cyclic amino group formed by a nitrogen contained in a ring having 2 to 5 carbon atoms and one other heteroatom, such as, for example, morpholino, thiomorpholino, piperazino.
By the terms xe2x80x9chaloxe2x80x9d or xe2x80x9chalogenxe2x80x9d in the present invention is meant fluoro, chloro, bromo, and iodo.
xe2x80x9cHaloalkylxe2x80x9d is intended to include both branched and straight-chain alkyl having the specified number of carbon atoms substituted with 1 or more halogens.
The term xe2x80x9cC2-C8 alkanoylxe2x80x9d means an acyl group with 2 to 8 carbon atoms in a linear, branched, or C3-C10 cycloalkyl arrangement, optionally substituted with 1 to 5 substituents independently selected at each occurrence from halogen, trifluoromethyl, OR7, NR8R9, CONR8R9, COOR7, or CN.
The term xe2x80x9cC1-C6 alkyl sulfonylxe2x80x9d means an alkylsulfonyl group containing 1 to 6 carbon atoms in a linear, branched, or C3-C7 cycloalkyl arrangement.
The term xe2x80x9csubstitutedxe2x80x9d means that one or more hydrogen on the designated atom is replaced by the specified group, provided that the valence on the designated atom is not exceeded, and that a chemically stable compound results from the substitution.
A stable compound is defined herein as one that can be isolated, characterized, and tested for biological activity.
The term xe2x80x9coxoxe2x80x9d (i.e. xe2x95x90O) indicates that two geminal hydrogen atoms are replaced by a double-bond oxygen group.
By xe2x80x9cheterocyclic corexe2x80x9d in the present invention is meant one of the following structures of formula Ia to XVa, where X, E, F, G, W, I, J, K, L, Q, R1, R3, R4, R15 and R16 are defined above. 
In the present invention, some of the groups specifically mentioned above are defined as follows: 
Unless specified, the point of attachment may occur in any stable point along the above-mentioned rings.
In the present invention, the term xe2x80x9cpotentxe2x80x9d in the context of NPY1 receptor antagonists qualifies a binding affinity with a Ki of less than 10 micromolar, preferably less than 1 micromolar, and more preferably less than 100 nanomolar in the human NPY1 binding assay.
In the present invention, the term xe2x80x9cselectivexe2x80x9d in the context of NPY1 receptor antagonists qualifies a binding affinity with a Ki in the human NPY1 binding assay that is 10-fold, preferably 100-fold, and more preferably 1000-fold, less than the Ki of the same compound measured in another receptor binding assay, in particular the NPY5 and CRF1 receptor binding assays. Binding assays for the NPY5 and CRF1 receptors have been described, for example, in J. Clin. Invest., 102, 2136 (1998) and in Endocrinology 116, 1653 (1985), respectively.
As the compounds of formula I-XV are antagonists of the Y1 receptor, they are of value in the treatment of a wide variety of clinical conditions which are characterized by the presence of an excess of neuropeptide Y. Thus, the invention provides methods for the treatment or prevention of a physiological disorder associated with an excess of neuropeptide Y, which method comprises administering to a mammal in need of said treatment an effective amount of a compound of formula I-XV or a pharmaceutically acceptable salt, solvate or prodrug thereof. The term xe2x80x9cphysiological disorder associated with an excess of neuropeptide Yxe2x80x9d encompasses those disorders associated with an inappropriate stimulation of neuropeptide Y receptors, regardless of the actual amount of neuropeptide Y present locally. These physiological disorders may include: disorders or diseases pertaining to the heart, blood vessels or the renal system, such as vasospasm, heart failure, shock, cardiac hypertrophy increased blood pressure, angina, myocardial infarction, sudden cardiac death, arrhythmia, peripheral vascular disease, and abnormal renal conditions such as impaired flow of fluid, abnormal mass transport, or renal failure; conditions related to increased sympathetic nerve activity for example, during or after coronary artery surgery, and operations and surgery in the gastrointestinal tract; cerebral diseases and diseases related to the central nervous system, such as cerebral infarction, neurodegeneration, epilepsy, stroke, and conditions related to stroke, cerebral vasospasm and hemorrhage, depression, anxiety, schizophrenia, and dementia; conditions related to pain or nociception; diseases related to abnormal gastrointestinal motility and secretion, such as different forms of ileus, urinary incontinence, and Crohn""s disease; abnormal drink and food intake disorders, such as obesity, anorexia, bulimia, and metabolic disorders; diseases related to sexual dysfunction and reproductive disorders; conditions or disorders associated with inflammation; respiratory diseases, such as asthma and conditions related to asthma and bronchoconstriction; and diseases related to abnormal hormone release, such as leutinizing hormone, growth hormone, insulin, and prolactin. See U.S. Pat. No. 5,504,094.
The compounds of general Formula I-XV may be administered orally, topically, parenterally, by inhalation or spray or rectally in dosage unit formulations containing conventional non-toxic pharmaceutically acceptable carriers, adjuvants and vehicles. The term parenteral as used herein includes subcutaneous injections, intravenous, intramuscular, intrasternal injection or infusion techniques. In addition, there is provided a pharmaceutical formulation comprising a compound of general Formula I-XV and a pharmaceutically acceptable carrier. One or more compounds of general Formula I-XV may be present in association with one or more non-toxic pharmaceutically acceptable carriers and/or diluents and/or adjuvants and if desired other active ingredients. The pharmaceutical compositions containing compounds of general Formula I-XV may be in a form suitable for oral use, for example, as tablets, troches, lozenges, aqueous or oily suspensions, dispersible powders or granules, emulsion, hard or soft capsules, or syrups or elixirs.
Compositions intended for oral use may be prepared according to any method known to the art for the manufacture of pharmaceutical compositions and such compositions may contain one or more agents selected from sweetening agents, flavoring agents, coloring agents and preserving agents in order to provide pharmaceutically elegant and palatable preparations. Tablets contain the active ingredient in admixture with non-toxic pharmaceutically acceptable excipients which are suitable for the manufacture of tablets. These excipients may be for example, inert diluents, such as calcium carbonate, sodium carbonate, lactose, calcium phosphate or sodium phosphate; granulating and disintegrating agents, for example, corn starch, or alginic acid; binding agents, for example starch, gelatin or acacia, and lubricating agents, for example magnesium stearate, stearic acid or talc. The tablets may be uncoated or they may be coated by known techniques to delay disintegration and absorption in the gastrointestinal tract and thereby provide a sustained action over a longer period. For example, a time delay material such as glyceryl monostearate or glyceryl distearate may be employed.
Formulations for oral use may also be presented as hard gelatin capsules wherein the active ingredient is mixed with an inert solid diluent, for example, calcium carbonate, calcium phosphate or kaolin, or as soft gelatin capsules wherein the active ingredient is mixed with water or an oil medium, for example peanut oil, liquid paraffin or olive oil.
Aqueous suspensions contain the active materials in admixture with excipients suitable for the manufacture of aqueous suspensions. Such excipients are suspending agents, for example sodium carboxymethylcellulose, methylcellulose, hydropropylmethylcellulose, sodium alginate, polyvinyl-pyrrolidone, gum tragacanth and gum acacia; dispersing or wetting agents may be a naturally-occurring phosphatide, for example, lecithin, or condensation products of an alkylene oxide with fatty acids, for example polyoxyethylene stearate, or condensation products of ethylene oxide with long chain aliphatic alcohols, for example heptadecaethyleneoxycetanol, or condensation products of ethylene oxide with partial esters derived from fatty acids and a hexitol such as polyoxyethylene sorbitol monooleate, or condensation products of ethylene oxide with partial esters derived from fatty acids and hexitol anhydrides, for example polyethylene sorbitan monooleate. The aqueous suspensions may also contain one or more preservatives, for example ethyl, or n-propyl p-hydroxybenzoate, one or more coloring agents, one or more flavoring agents, and one or more sweetening agents, such as sucrose or saccharin.
Oily suspensions may be formulated by suspending the active ingredients in a vegetable oil, for example arachid oil, olive oil, sesame oil or coconut oil, or in a mineral oil such as liquid paraffin. The oily suspensions may contain a thickening agent, for example beeswax, hard paraffin or cetyl alcohol. Sweetening agents such as those set forth above, and flavoring agents may be added to provide palatable oral preparations. These compositions may be preserved by the addition of an anti-oxidant such as ascorbic acid.
Dispersible powders and granules suitable for preparation of an aqueous suspension by the addition of water provide the active ingredient in admixture with a dispersing or wetting agent, suspending agent and one or more preservatives. Suitable dispersing or wetting agents and suspending agents are exemplified by those already mentioned above. Additional excipients, for example sweetening, flavoring and coloring agents, may also be present.
Pharmaceutical compositions of the invention may also be in the form of oil-in-water emulsions. The oily phase may be a vegetable oil, for example olive oil or arachid oil, or a mineral oil, for example liquid paraffin or mixtures of these. Suitable emulsifying agents may be naturally-occurring gums, for example gum acacia or gum tragacanth, naturally-occurring phosphatides, for example soy bean, lecithin, and esters or partial esters derived from fatty acids and hexitol, anhydrides, for example sorbitan monooleate, and condensation products of the said partial esters with ethylene oxide, for example polyoxyethylene sorbitan monooleate. The emulsions may also contain sweetening and flavoring agents.
Syrups and elixirs may be formulated with sweetening agents, for example glycerol, propylene glycol, sorbitol or sucrose. Such formulations may also contain a demulcent, a preservative and flavoring and coloring agents. The pharmaceutical compositions may be in the form of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to the known art using those suitable dispersing or wetting agents and suspending agents which have been mentioned above. The sterile injectable preparation may also be sterile injectable solution or suspension in a non-toxic parentally acceptable diluent or solvent, for example as a solution in 1,3-butanediol. Among the acceptable vehicles and solvents that may be employed are water, Ringer""s solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose any bland fixed oil may be employed including synthetic mono- or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables.
The compounds of general Formula I-XV may also be administered in the form of suppositories for rectal administration of the drug. These compositions can be prepared by mixing the drug with a suitable non-irritating excipient which is solid at ordinary temperatures but liquid at the rectal temperature and will therefore melt in the rectum to release the drug. Such materials are cocoa butter and polyethylene glycols.
Compounds of general Formula I-XV may be administered parenterally in a sterile medium. The drug, depending on the vehicle and concentration used, can either be suspended or dissolved in the vehicle. Advantageously, adjuvants such as local anesthetics, preservatives and buffering agents can be dissolved in the vehicle.
Dosage levels of the order of from about 0.1 mg to about 50 mg per kilogram of body weight per day are useful in the treatment of the above-indicated conditions (about 0.5 mg to about 3 g per patient per day), although in some circumstances higher amounts, fo example upto 140 mg/kg/day may be appropriate. The amount of active ingredient that may be combined with the carrier materials to produce a single dosage form will vary depending upon the host treated and the particular mode of administration. Dosage unit forms will generally contain between from about 1 mg to about 500 mg of an active ingredient.
Frequency of dosage may also vary depending on the compound used and the particular disease treated. However, for treatment of most eating disorders, a dosage regimen of 4 times daily or less is preferred. For the treatment of stress and depression a dosage regimen of 1 or 2 times daily is particularly preferred.
It will be understood, however, that the specific dose level for any particular patient will depend upon a variety of factors including the activity of the specific compound employed, the age, body weight, general health, sex, diet, time of administration, route of administration, and rate of excretion, drug combination and the severity of the particular disease undergoing therapy.
Preferred compounds of the invention will have certain pharmacological properties. Such properties include, but are not limited to oral bioavailability, low toxicity, low serum protein binding and desirable in vitro and in vivo half-lives. Penetration of the blood brain barrier for compounds used to treat CNS disorders is necessary, while low brain levels of compounds used to treat peripheral disorders are often preferred.
Assays may be used to predict these desirable pharmacological properties. Assays used to predict bioavailability include transport across human intestinal cell monolayers, including Caco-2 cell monolayers. Toxicity to cultured hepatocytes may be used to predict compound toxicity. Penetration of the blood brain barrier of a compound in humans may be predicted from the brain levels of the compound in laboratory animals given the compound intravenously.
Serum protein binding may be predicted from albumin binding assays. Such assays are described in a review by Oravcova, et al. (Journal of Chromatography B 1996, 677, 1-27).
Compound half-life is inversely proportional to the frequency of dosage of a compound. In vitro half-lives of compounds may be predicted from assays of microsomal half-life as described by Kuhnz and Gieschen (Drug Metabolism and Disposition 1998, 26, 1120-1127).
As discussed above, preferred compounds of the invention exhibit good activity in standard in vitro NPY receptor binding assays, specifically the assay as specified in Example 261, which follows. References herein to xe2x80x9cstandard in vitro receptor binding assayxe2x80x9d are intended to refer to that protocol as defined in Example 261 which follows. Generally preferred compounds of the invention exhibit a Ki of about 1 micromolar or less, still more preferably and Ki of about 100 nanomolar or less even more preferably an Ki of about 10 nanomolar or less or even 1 nanomolar or less in such a defined standard in vitro NPY receptor binding assay as exemplified by Example 261 which follows.
In appropriate case, the compounds of the invention may be employed in combination with other active agents. The invention therefore also provides pharmaceutical combination compositions comprising a therapeutically effective amount of a composition comprising: (a) first compound, said first compound being a compound as described above a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; and (b) a second compound, said second compound being a xcex23 agonist, a thyromimetic, an eating behavior modifying agent or a NPY antagonist; and a pharmaceutical carrier, vehicle, diluent. To this end therefore the invention also provides a kit comprising: (a) first compound, said first compound being a compound as described above, a prodrug thereof, or a pharmaceutically acceptable salt of said compound or of said prodrug; (b) a second compound, said second compound being a xcex23 agonist, a thyromimetic, an eating behavior modifying agent or a NPY antagonist; and a pharmaceutical carrier, vehicle, diluent; and (c) means for containing said first and second unit dosage forms wherein the amounts of the first and second compounds result in a therapeutic effect.
The preparation of these heterocyclic cores, identified in formula II-XV, can be carried out according to the methods described in the following references and those cited therein:
Formula II: WO 9413676, WO 9534563, WO 9845295, EP 729758, J. Med. Chem., 40(11), 1749-1754 (1997), Bioorg. Med. Chem. Lett., 9(7), 967-972 (1999), J. Med. Chem., 42(5), 819-832 (1999); J. Med. Chem. 42(5), 833-848 (1999);
Formula III: WO 9635689, WO 9729110, WO 9808847, WO 9847903, WO 9940091, U.S. Pat. No. 5,664,057;
Formula IV: WO 9413677, WO 9534563, EP 0729758;
Formula V: WO 9533750, J. Med. Chem. 42(5), 833-848 (1999); Bioorg. Med. Chem. Lett., 9(7), 967-972 (1999);
Formula VI: WO 9808847, WO 9829397;
Formula VII: EP 239191, U.S. Pat. No. 5,273,608;
Formula VIII: U.S. Pat. No. 5,273,608;
Formula IX: WO 9510506, WO 9735539, WO 9808847, WO 9842706, J. Med. Chem. 42(5), 833-848 (1999);
Formula X: WO 9808847, WO 9835967;
Formula XI: WO 9533750, Bioorg. Med. Chem. Lett., 9(7), 967-972 (1999);
Formula XII: WO 9808847, WO 9835967;
Formula XIII: WO 9744038;
Formula XIV: WO 9808846; WO 9829397, WO 9835967, WO 9847874, WO 9912908;
Formula XV: WO 9510506, WO 9533750, WO 9714684, WO 9735580, WO 9842699, EP 778277, J. Med. Chem. 39(22), 4358-4360 (1996), J. Med. Chem. 42(5), 805-818 (1999), J. Med. Chem. 42(5), 833-848 (1999);
An illustration of preparation methods of compounds of the present invention is given in the Schemes below. In particular displacement of a leaving group Z, as in formula 10 (scheme 1) by the appropriate substituted amine or appropriate substitution of an heterocyclic amino group, as in formula 21 (scheme 7), provides general methods to convert the heterocyclic cores of the present invention into compounds that potently interact with the NPY1 receptor. Such transformations may require several consecutive chemical steps. Those having skill in the art will recognize that the starting materials may be varied and additional steps employed to produce compounds encompassed by the present invention. The disclosures of all articles and references mentioned in this application, including patents, are incorporated herein by reference. 
As illustrated in scheme 1, compounds of formula A can be prepared from intermediate compounds of formula 10, where Z is halogen (preferably chloro or bromo), alkane sulfonyloxy, aryl sulfonyloxy or haloalkane sulfonyloxy, and where R1, R2, R4, R5, R6, X, Y, A, and B are defined above, using the procedures outlined below.
Compounds of formula 10 react with an amine of formula H2Nxe2x80x94Axe2x80x94Bxe2x80x94N[R6]xe2x80x94R5, where A, B, R5 and R6 are defined as above, in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 250xc2x0 C. to generate compounds of formula A. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbons) (preferably methanol, ethanol, or tert-butanol), lower alkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes (1-10 carbons and 1-10 halogens) (preferably CH2Cl2). Preferred reaction temperatures range from 0xc2x0 C. to 140xc2x0 C. 
Alternatively, as illustrate in scheme 2, compounds of formula A can be obtained by first reacting a compound of formula 10 with an amino alcohol of formula H2Nxe2x80x94Axe2x80x94Bxe2x80x94OH, where A and B are defined as above, in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 250xc2x0 C. to generate intermediates of formula 11. Reacting a compound of formula 11 with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 250xc2x0 C. to afford products of formula 12a (where Z is halogen, alkane sulfonyloxy, aryl sulfonyloxy or haloalkane sulfonyloxy) or 12b when A and B are both CH2 and X is CR14. Halogenating agents include, but are not limited to, SOCl2, POCl3, PCl3, PCl5, POBr3, PBr3, PBr5, CCl4/PPH3. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (preferably methanesulfonyl chloride or methanesulfonic anhydride), aryl sulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride), or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines (preferably DBU), anilines (preferably N-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes with 1-10 carbons and 1-10 halogens (preferably CH2Cl2). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 100xc2x0 C. Compounds of formula 12a or 12b can then be reacted with an amine of formula HN[R6]xe2x80x94R5, where R5 and R6 are defined as above, to give a compound of formula A Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbons) (preferably methanol, ethanol, or tert-butanol), lower alkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes (1-10 carbons and 1-10 halogens) (preferably CH2Cl2). Preferred reaction temperatures range from 0xc2x0 C.C to 140xc2x0 C. 
A subset of compounds of formula A, described under formula A1 (scheme 3), can be obtained by first reacting a compound of formula 10 with a diamine of formula H2Nxe2x80x94Axe2x80x94Bxe2x80x94NH2, where A and B are defined as above, in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 250xc2x0 C. to generate intermediates of formula 13. Reaction of a compound of formula 13 with a ketone of Formula Raxe2x80x94Cxe2x95x90Oxe2x80x94Rb in the presence of a reducing agent provides a compound of formula A1, where the grouping Raxe2x80x94CHxe2x80x94Rb corresponds to R5 in formula A, as defined above. Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane (preferably complexed with dimethyl sulfide or tetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride), dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane (preferably complexed with dimethyl amine). Inert solvents may include, but are not limited to, alkyl alcohols (1-6 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9278xc2x0 C. to 100xc2x0 C. 
Alternatively, a subset of compounds of formula A, described under formula A2 (scheme 4), can be obtained by first reacting a compound of formula 13 with an activated acid of formula Rcxe2x80x94Cxe2x95x90Oxe2x80x94Z, where Z is halo (preferably chloro), O-acyl (preferably Oxe2x80x94Cxe2x95x90Oxe2x80x94Rc), in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 250xc2x0 C. to generate an amide intermediate of formula 14. Reaction of a compound of formula 14 with a reducing agent provides a compound of formula A2, where the grouping Rcxe2x80x94CH2 corresponds to R5 in formula A, as defined above. Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane (preferably complexed with dimethyl sulfide or tetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride), dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane (preferably complexed with dimethyl amine). Inert solvents may include, but are not limited to, alkyl alcohols (1-6 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9278xc2x0 C. to 100xc2x0 C. 
Alternatively, a subset of compounds of formula A, described under formula A3 (scheme 5), can be obtained by first reacting a compound of formula 10 with an amine of formula H2Nxe2x80x94Axe2x80x94CH(ORc)(ORd), where A is defined above, and Rc and Rd are C1-C6 lower alkyls or, taken together, complete a ketal group, such as, for example a dioxane or dioxolane group, in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 250xc2x0 C. to generate compounds of formula 15. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbons) (preferably methanol, ethanol, or tert-butanol), lower alkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes (1-10 carbons and 1-10 halogens) (preferably CH2Cl2). Compounds of formula 15 react with a protic acid in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 250xc2x0 C., followed by aqueous work-up to generate compounds of formula 16. Inert solvents may include, but are not limited to dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes (1-10 carbons and 1-10 halogens) (preferably CH2Cl2). Protic acids include, but are not limited to, formic acid, acetic acid, trifluoroacetic acid, hydrochloric acid, methane sulfonic acid. Alternatively, compounds of formula 16 can be obtained by oxidation of compounds of formula 11 where B=CH2. Oxidizing agents include, but are not limited to, transition metal oxides, such as CrO3 or MnO2, pyridine-chromium complexes, such as CrO3.C5H5N, pyridinium dichromate or pyridinium chlorochromate, or an oxalyl chloride-DMSO-triethylamine reagent (Swern oxidation). Compounds of formula 16 react with amines of formula H2Nxe2x80x94R5, where R5 is defined above, in the presence of a reducing agent in the presence or absence of an inert solvent in the presence or absence of a protic acid at temperatures ranging from xe2x88x9278xc2x0 C. to 100xc2x0 C., to give compounds of formula A3. Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane (preferably complexed with dimethyl sulfide or tetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride), dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane (preferably complexed with dimethyl amine). Inert solvents may include, but are not limited to, alkyl alcohols (1-6 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene).
Compounds of formula 10, encompassing the heterocyclic cores of formula I-XV, are prepared according to procedures described in the references listed below.
Compounds of formula 10a, used as starting material for the preparation of compounds of formula I, can be obtained according to scheme 6. 
Compounds of formula 17, where E, F, and G are defined above and Z is a halogen, react with a compound of formula R4xe2x80x94CH2xe2x80x94CN, where R4 is defined above, in the presence of base, in the presence or absence of an inert solvent, at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 100xc2x0 C., to generate compounds of formula 18. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or dialkylsulfoxides (preferably dimethylsulfoxide). Preferred reaction temperatures range from 0xc2x0 C. to 100xc2x0 C. Compounds of formula 18 then react with a compound of formula Zxe2x80x94CH2xe2x80x94COORc, where Z is halogen (preferably chloro or bromo), alkane sulfonyloxy, aryl sulfonyloxy or haloalkane sulfonyloxy and Rc is C1-C6 alkyl in the presence of base, in the presence or absence of an inert solvent, at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 100xc2x0 C., to generate compounds of formula 19. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or dialkylsulfoxides (preferably dimethylsulfoxide). Preferred reaction temperatures range from 0xc2x0 C. to 100xc2x0 C. Compounds of formula 20, where X is CR14 and R1 is defined above, can be obtained in two consecutive steps from compounds of formula 19 can be first reacted with a compound of formula R1C(ORc)xe2x80x94CH2xe2x80x94R14, where Rc is methyl or ethyl, in the presence of base, in the presence or absence of an inert solvent, at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 100xc2x0 C., to generate an non-isolated imine intermediate. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or dialkylsulfoxides (preferably dimethylsulfoxide). Preferred reaction temperatures range from 0xc2x0 C. to 100xc2x0 C. In a second step, the imine intermediates are cyclized to a compound of formula 20 (X=CR14) in the presence of base, in the presence or absence of an inert solvent, at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 100xc2x0 C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), or dialkylsulfoxides (preferably dimethylsulfoxide). Preferred reaction temperatures range from 0xc2x0 C. to 100xc2x0 C.
Compounds of formula 20, where X is N and R1 is defined above, can be obtained by reacting compounds of formula 19 with a compound of formula R1xe2x80x94Cxe2x95x90Oxe2x80x94Rc, and Rc is halogen, cyano, lower alkoxy (1-6 carbons), or lower alkanoyloxy (1-6 carbons), in the presence of a base in an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 200xc2x0 C. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal hydroxides, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines (preferably DBU), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbons) (preferably methanol, ethanol, or tert-butanol), lower alkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene). Compounds of formula 10a, where Z is halogen, alkane sulfonyloxy, aryl sulfonyloxy or haloalkane sulfonyloxy and X is N, can be prepared by reacting a compound of formula 20 with a halogenating agent or sulfonylating agent in the presence or absence of a base in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 250xc2x0 C. Halogenating agents include, but are not limited to, SOCl2, POCl3, PCl3, PCl5, POBr3, PBr3, or PBr5. Sulfonylating agents include, but are not limited to, alkanesulfonyl halides or anhydrides (preferably methanesulfonyl chloride or methanesulfonic anhydride), aryl sulfonyl halides or anhydrides (such as p-toluenesulfonyl chloride or anhydride), or haloalkylsulfonyl halides or anhydrides (preferably trifluoromethanesulfonic anhydride). Bases may include, but are not limited to, trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines (preferably DBU), anilines (preferably N-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes with 1-10 carbons and 1-10 halogens (preferably CH2Cl2). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 100xc2x0 C.
Alternatively, some of the compounds of formula A can be obtained from compounds of formula 21, as illustrated in scheme 7. 
Compounds of formula 21, where X, R1 and R4 are defined above, react with a compound of formula Zxe2x80x94Bxe2x80x94(Cxe2x95x90O)xe2x80x94Rc, where B is defined above, Z is halogen (preferably chloro or bromo), alkane sulfonyloxy, aryl sulfonyloxy or haloalkane sulfonyloxy, and Rc is halogen, cyano, lower alkoxy (1-6 carbons), or lower alkanoyloxy (1-6 carbons), in the presence or absence of a base, in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 200xc2x0 C., to produce compounds of formula 22. Bases may include, but are not limited to, trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), bicyclic amidines (preferably DBU), anilines (preferably N-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, lower alkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes with 1-10 carbons and 1-10 halogens (preferably CH2Cl2). Preferred reaction temperatures range from xe2x88x9220xc2x0 C. to 100xc2x0 C.
Amides of formula 22 can be reacted with an amine of formula NH[R6]R5, where R6 and R5 are defined above, in the presence or absence of a base, in the presence or absence of an inert solvent at reaction temperatures ranging from xe2x88x9278xc2x0 C. to 200xc2x0 C., to produce compounds of formula 23. Bases may include, but are not limited to, alkali metal hydrides (preferably sodium hydride), alkali metal alkoxides (1-6 carbons) (preferably sodium methoxide, sodium ethoxide, or sodium tert-butoxide), alkaline earth metal hydrides, alkali metal dialkylamides (preferably lithium diisopropylamide), alkali metal carbonates, alkali metal bicarbonates, alkali metal bis-(trialkylsilyl)amides (preferably lithium or sodium (trimethylsilyl)amide), trialkylamines (preferably N,N-di-isopropyl-N-ethyl amine or triethylamine), arylamines (preferably 4-dimethyl aniline), or heteroaromatic amines (preferably pyridine). Inert solvents may include, but are not limited to, alkyl alcohols (1-8 carbons) (preferably methanol, ethanol, or tert-butanol), lower alkanenitriles (1-6 carbons) (preferably acetonitrile), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), N,N-dialkylformamides (preferably dimethyl formamide), N,N-dialkylacetamides (preferably dimethyl acetamide), cyclic amides (preferably N-methylpyrrolidin-2-one), dialkylsulfoxides (preferably dimethylsulfoxide), aromatic hydrocarbons (preferably benzene or toluene), or haloalkanes (1-10 carbons and 1-10 halogens) (preferably CH2Cl2). Preferred reaction temperatures range from 0xc2x0 C. to 140xc2x0 C.
Compounds of formula 23 can be reacted with a reducing agent in the presence or absence of an inert solvent to provide compounds of formula A, as defined above. Reducing agents include, but are not limited to, alkali metal or alkaline earth metal borohydrides (preferably lithium or sodium borohydride), borane (preferably complexed with dimethyl sulfide or tetrahydrofuran), dialkylboranes (such as di-isoamylborane), alkali metal aluminum hydrides (preferably lithium aluminum hydride), alkali metal (trialkoxy)aluminum hydrides (such as triethoxyaluminum hydride), dialkyl aluminum hydrides (such as di-isobutyl aluminum hydride), alane (preferably complexed with dimethyl amine). Inert solvents may include, but are not limited to, alkyl alcohols (1-6 carbons) (preferably methanol, ethanol, or tert-butanol), dialkyl ethers (preferably diethyl ether), cyclic ethers (preferably tetrahydrofuran or 1,4-dioxane), aromatic hydrocarbons (preferably benzene or toluene). Preferred reaction temperatures range from xe2x88x9278xc2x0 C. to 100xc2x0 C.
Alternatively, compounds of formula 22 can be reduced first, under experimental conditions similar to those used for the conversion of compounds of formula 23 to compounds of formula A, to generate compounds of formula 24. Compounds of formula 24 can then be reacted with compounds of formula NH[R6]R5, as defined above, under experimental conditions similar to those used for the conversion of compounds of formula 22 to compounds of formula 23, to generate compounds of formula A.
Other compounds of formula 10 and of formula 21, used as starting material for the preparation of compounds of formula IIxe2x80x94XV, can be obtained according to procedures described in the following references:
Formula II: WO 9413676, WO 9534563, WO 9845295, EP 729758, J. Med. Chem., 40(11), 1749-1754 (1997), Bioorg. Med. Chem. Lett., 9(7), 967-972 (1999), J. Med. Chem., 42(5), 819-832 (1999); J. Med. Chem. 42(5), 833-848 (1999);
Formula III: WO 9635689, WO 9729110, WO 9808847, WO 9847903, WO 9940091, U.S. Pat. No. 5,664,057;
Formula IV: WO 9413677, WO 9534563, EP 0729758;
Formula V: WO 9533750, J. Med. Chem. 42(5), 833-848 (1999); Bioorg. Med. Chem. Lett., 9(7), 967-972 (1999);
Formula VI: WO 9808847, WO 9829397;
Formula VII: EP 239191, U.S. Pat. No. 5,273,608;
Formula VIII: U.S. Pat. No. 5,273,608;
Formula IX: WO 9510506, WO 9735539, WO 9808847, WO 9842706, J. Med. Chem. 42(5), 833-848 (1999);
Formula X: WO 9808847, WO 9835967;
Formula XI: WO 9533750, Bioorg. Med. Chem. Lett., 9(7), 967-972 (1999);
Formula XII: WO 9808847, WO 9835967;
Formula XIII: WO 9744038;
Formula XIV: WO 9808846; WO 9829397, WO 9835967, WO 9847874, WO 9912908;
Formula XV: WO 9510506, WO 9533750, WO 9714684, WO 9735580, WO 9842699, EP 778277, J. Med. Chem. 39(22), 4358-4360 (1996), J. Med. Chem. 42(5), 805-818 (1999), J. Med. Chem. 42(5), 833-848 (1999).